Proline-rich tyrosine kinase 2 (Pyk2) regulates IGF-I-induced cell motility and invasion of urothelial carcinoma cells
The insulin-like growth factor receptor I (IGF-IR) plays an essential role in transformation by promoting cell growth and protecting cancer cells from apoptosis. We have recently demonstrated that the IGF-IR is overexpressed in invasive bladder cancer tissues and promotes motility and invasion of ur...
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| Veröffentlicht in: | PloS one 2012-06, Vol.7 (6), p.e40148 |
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| creator | Genua, Marco Xu, Shi-Qiong Buraschi, Simone Peiper, Stephen C Gomella, Leonard G Belfiore, Antonino Iozzo, Renato V Morrione, Andrea |
| description | The insulin-like growth factor receptor I (IGF-IR) plays an essential role in transformation by promoting cell growth and protecting cancer cells from apoptosis. We have recently demonstrated that the IGF-IR is overexpressed in invasive bladder cancer tissues and promotes motility and invasion of urothelial carcinoma cells. These effects require IGF-I-induced Akt- and MAPK-dependent activation of paxillin. The latter co-localizes with focal adhesion kinases (FAK) at dynamic focal adhesions and is critical for promoting motility of urothelial cancer cells. FAK and its homolog Proline-rich tyrosine kinase 2 (Pyk2) modulate paxillin activation; however, their role in regulating IGF-IR-dependent signaling and motility in bladder cancer has not been established. In this study we demonstrate that FAK was not required for IGF-IR-dependent signaling and motility of invasive urothelial carcinoma cells. On the contrary, Pyk2, which was strongly activated by IGF-I, was critical for IGF-IR-dependent motility and invasion and regulated IGF-I-dependent activation of the Akt and MAPK pathways. Using immunofluorescence and AQUA analysis we further discovered that Pyk2 was overexpressed in bladder cancer tissues as compared to normal tissue controls. Significantly, in urothelial carcinoma tissues there was increased Pyk2 localization in the nuclei as compared to normal tissue controls. These results provide the first evidence of a specific Pyk2 activity in regulating IGF-IR-dependent motility and invasion of bladder cancer cells suggesting that Pyk2 and the IGF-IR may play a critical role in the invasive phenotype in urothelial neoplasia. In addition, Pyk2 and the IGF-IR may serve as novel biomarkers with diagnostic and prognostic significance in bladder cancer. |
| doi_str_mv | 10.1371/journal.pone.0040148 |
| format | Article |
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We have recently demonstrated that the IGF-IR is overexpressed in invasive bladder cancer tissues and promotes motility and invasion of urothelial carcinoma cells. These effects require IGF-I-induced Akt- and MAPK-dependent activation of paxillin. The latter co-localizes with focal adhesion kinases (FAK) at dynamic focal adhesions and is critical for promoting motility of urothelial cancer cells. FAK and its homolog Proline-rich tyrosine kinase 2 (Pyk2) modulate paxillin activation; however, their role in regulating IGF-IR-dependent signaling and motility in bladder cancer has not been established. In this study we demonstrate that FAK was not required for IGF-IR-dependent signaling and motility of invasive urothelial carcinoma cells. On the contrary, Pyk2, which was strongly activated by IGF-I, was critical for IGF-IR-dependent motility and invasion and regulated IGF-I-dependent activation of the Akt and MAPK pathways. Using immunofluorescence and AQUA analysis we further discovered that Pyk2 was overexpressed in bladder cancer tissues as compared to normal tissue controls. Significantly, in urothelial carcinoma tissues there was increased Pyk2 localization in the nuclei as compared to normal tissue controls. These results provide the first evidence of a specific Pyk2 activity in regulating IGF-IR-dependent motility and invasion of bladder cancer cells suggesting that Pyk2 and the IGF-IR may play a critical role in the invasive phenotype in urothelial neoplasia. In addition, Pyk2 and the IGF-IR may serve as novel biomarkers with diagnostic and prognostic significance in bladder cancer.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0040148</identifier><identifier>PMID: 22859931</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>AKT protein ; Antigens ; Apoptosis ; Biology ; Biomarkers ; Bladder ; Bladder cancer ; Breast cancer ; Cancer ; Carcinoma ; Carcinoma - enzymology ; Carcinoma - genetics ; Carcinoma - metabolism ; Carcinoma - pathology ; Cell cycle ; Cell growth ; Cell Line, Tumor ; Cell Movement - genetics ; Diagnostic systems ; Endocrinology ; Fibroblasts ; Focal adhesion kinase ; Focal Adhesion Kinase 1 - genetics ; Focal Adhesion Kinase 1 - metabolism ; Focal Adhesion Kinase 2 - genetics ; Focal Adhesion Kinase 2 - metabolism ; Focal Adhesions - genetics ; Focal Adhesions - metabolism ; Genetic transformation ; GRB2 Adaptor Protein - genetics ; GRB2 Adaptor Protein - metabolism ; Homology ; Humans ; Immunofluorescence ; Insulin ; Insulin Receptor Substrate Proteins - genetics ; Insulin Receptor Substrate Proteins - metabolism ; Insulin-like growth factor I ; Insulin-Like Growth Factor I - genetics ; Insulin-Like Growth Factor I - metabolism ; Insulin-like growth factors ; Invasiveness ; Kinases ; Localization ; MAP kinase ; Medical prognosis ; Medicine ; Mitogen-Activated Protein Kinases - genetics ; Mitogen-Activated Protein Kinases - metabolism ; Motility ; Neoplasm Invasiveness ; Nuclei ; Pathology ; Paxillin ; Paxillin - genetics ; Paxillin - metabolism ; Phenols (Class of compounds) ; Proline ; Proline-rich tyrosine kinase 2 ; Prostate cancer ; Protein-tyrosine kinase ; Proto-Oncogene Proteins c-akt - genetics ; Proto-Oncogene Proteins c-akt - metabolism ; Receptor, IGF Type 1 - genetics ; Receptor, IGF Type 1 - metabolism ; Rodents ; Signal Transduction - genetics ; Signaling ; Tissues ; Transformation ; Tumors ; Tyrosine ; Urinary bladder ; Urinary Bladder Neoplasms - enzymology ; Urinary Bladder Neoplasms - genetics ; Urinary Bladder Neoplasms - metabolism ; Urinary Bladder Neoplasms - pathology ; Urology ; Urothelial cancer ; Urothelial carcinoma ; Urothelium - enzymology ; Urothelium - metabolism ; Urothelium - pathology</subject><ispartof>PloS one, 2012-06, Vol.7 (6), p.e40148</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012 Genua et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Genua et al. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c659t-1f3cf797b22cba4aba9d9b760e886178501ce4e6ef7632e43e8ab45ba78e81673</citedby><cites>FETCH-LOGICAL-c659t-1f3cf797b22cba4aba9d9b760e886178501ce4e6ef7632e43e8ab45ba78e81673</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408023/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408023/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22859931$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Genua, Marco</creatorcontrib><creatorcontrib>Xu, Shi-Qiong</creatorcontrib><creatorcontrib>Buraschi, Simone</creatorcontrib><creatorcontrib>Peiper, Stephen C</creatorcontrib><creatorcontrib>Gomella, Leonard G</creatorcontrib><creatorcontrib>Belfiore, Antonino</creatorcontrib><creatorcontrib>Iozzo, Renato V</creatorcontrib><creatorcontrib>Morrione, Andrea</creatorcontrib><title>Proline-rich tyrosine kinase 2 (Pyk2) regulates IGF-I-induced cell motility and invasion of urothelial carcinoma cells</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The insulin-like growth factor receptor I (IGF-IR) plays an essential role in transformation by promoting cell growth and protecting cancer cells from apoptosis. We have recently demonstrated that the IGF-IR is overexpressed in invasive bladder cancer tissues and promotes motility and invasion of urothelial carcinoma cells. These effects require IGF-I-induced Akt- and MAPK-dependent activation of paxillin. The latter co-localizes with focal adhesion kinases (FAK) at dynamic focal adhesions and is critical for promoting motility of urothelial cancer cells. FAK and its homolog Proline-rich tyrosine kinase 2 (Pyk2) modulate paxillin activation; however, their role in regulating IGF-IR-dependent signaling and motility in bladder cancer has not been established. In this study we demonstrate that FAK was not required for IGF-IR-dependent signaling and motility of invasive urothelial carcinoma cells. On the contrary, Pyk2, which was strongly activated by IGF-I, was critical for IGF-IR-dependent motility and invasion and regulated IGF-I-dependent activation of the Akt and MAPK pathways. Using immunofluorescence and AQUA analysis we further discovered that Pyk2 was overexpressed in bladder cancer tissues as compared to normal tissue controls. Significantly, in urothelial carcinoma tissues there was increased Pyk2 localization in the nuclei as compared to normal tissue controls. These results provide the first evidence of a specific Pyk2 activity in regulating IGF-IR-dependent motility and invasion of bladder cancer cells suggesting that Pyk2 and the IGF-IR may play a critical role in the invasive phenotype in urothelial neoplasia. In addition, Pyk2 and the IGF-IR may serve as novel biomarkers with diagnostic and prognostic significance in bladder cancer.</description><subject>AKT protein</subject><subject>Antigens</subject><subject>Apoptosis</subject><subject>Biology</subject><subject>Biomarkers</subject><subject>Bladder</subject><subject>Bladder cancer</subject><subject>Breast cancer</subject><subject>Cancer</subject><subject>Carcinoma</subject><subject>Carcinoma - enzymology</subject><subject>Carcinoma - genetics</subject><subject>Carcinoma - metabolism</subject><subject>Carcinoma - pathology</subject><subject>Cell cycle</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Cell Movement - genetics</subject><subject>Diagnostic systems</subject><subject>Endocrinology</subject><subject>Fibroblasts</subject><subject>Focal adhesion kinase</subject><subject>Focal Adhesion Kinase 1 - genetics</subject><subject>Focal Adhesion Kinase 1 - metabolism</subject><subject>Focal Adhesion Kinase 2 - genetics</subject><subject>Focal Adhesion Kinase 2 - metabolism</subject><subject>Focal Adhesions - genetics</subject><subject>Focal Adhesions - metabolism</subject><subject>Genetic transformation</subject><subject>GRB2 Adaptor Protein - genetics</subject><subject>GRB2 Adaptor Protein - metabolism</subject><subject>Homology</subject><subject>Humans</subject><subject>Immunofluorescence</subject><subject>Insulin</subject><subject>Insulin Receptor Substrate Proteins - genetics</subject><subject>Insulin Receptor Substrate Proteins - metabolism</subject><subject>Insulin-like growth factor I</subject><subject>Insulin-Like Growth Factor I - genetics</subject><subject>Insulin-Like Growth Factor I - metabolism</subject><subject>Insulin-like growth factors</subject><subject>Invasiveness</subject><subject>Kinases</subject><subject>Localization</subject><subject>MAP kinase</subject><subject>Medical prognosis</subject><subject>Medicine</subject><subject>Mitogen-Activated Protein Kinases - genetics</subject><subject>Mitogen-Activated Protein Kinases - metabolism</subject><subject>Motility</subject><subject>Neoplasm Invasiveness</subject><subject>Nuclei</subject><subject>Pathology</subject><subject>Paxillin</subject><subject>Paxillin - genetics</subject><subject>Paxillin - metabolism</subject><subject>Phenols (Class of compounds)</subject><subject>Proline</subject><subject>Proline-rich tyrosine kinase 2</subject><subject>Prostate cancer</subject><subject>Protein-tyrosine kinase</subject><subject>Proto-Oncogene Proteins c-akt - genetics</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Receptor, IGF Type 1 - genetics</subject><subject>Receptor, IGF Type 1 - metabolism</subject><subject>Rodents</subject><subject>Signal Transduction - genetics</subject><subject>Signaling</subject><subject>Tissues</subject><subject>Transformation</subject><subject>Tumors</subject><subject>Tyrosine</subject><subject>Urinary bladder</subject><subject>Urinary Bladder Neoplasms - enzymology</subject><subject>Urinary Bladder Neoplasms - genetics</subject><subject>Urinary Bladder Neoplasms - metabolism</subject><subject>Urinary Bladder Neoplasms - pathology</subject><subject>Urology</subject><subject>Urothelial cancer</subject><subject>Urothelial carcinoma</subject><subject>Urothelium - enzymology</subject><subject>Urothelium - metabolism</subject><subject>Urothelium - pathology</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNptUltvFCEYnRiNrdV_YJTEl_owK3eYF5OmsXWTJvZBnwnDMLtsGagws8n-e9nutOmahgfg45zzXThV9RHBBSICfdvEKQXtF_cx2AWEFCIqX1WnqCG45hiS18_OJ9W7nDcQMiI5f1udYCxZ0xB0Wm1vU_Qu2Do5swbjLsVcbuDOBZ0twOD8dneHv4JkV5PXo81geX1VL2sXusnYDhjrPRji6Lwbd0CHDriw1dnFAGIPphTHtfVOe2B0Mi7EQT9Q8vvqTa99th_m_az6c_Xj9-XP-ubX9fLy4qY2nDVjjXpietGIFmPTaqpb3XRNKzi0UnIkJIPIWGq57QUn2FJipW4pa7WQViIuyFn1-aB772NW88iyQgQzSBkUTUEsD4gu6o26T27QaaeiduohENNK6TQ6461ihFpTknWQYcp71lDeEYFLgRQaJGXR-j5nm9rBdsaGMWl_JHr8EtxareJWEQolxKQInM8CKf6dbB7V4PJ-YDrYOJW6IUGofCjb1_3lP-jL3c2olS4NuNDHktfsRdUFFQJCySUrqMULqLI6OzhT_NW7Ej8i0APBFL_kZPunHhFUe3c-FqP27lSzOwvt0_P5PJEe7Uj-AePO4XI</recordid><startdate>20120628</startdate><enddate>20120628</enddate><creator>Genua, Marco</creator><creator>Xu, Shi-Qiong</creator><creator>Buraschi, Simone</creator><creator>Peiper, Stephen C</creator><creator>Gomella, Leonard G</creator><creator>Belfiore, Antonino</creator><creator>Iozzo, Renato V</creator><creator>Morrione, Andrea</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20120628</creationdate><title>Proline-rich tyrosine kinase 2 (Pyk2) regulates IGF-I-induced cell motility and invasion of urothelial carcinoma cells</title><author>Genua, Marco ; Xu, Shi-Qiong ; Buraschi, Simone ; Peiper, Stephen C ; Gomella, Leonard G ; Belfiore, Antonino ; Iozzo, Renato V ; Morrione, Andrea</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c659t-1f3cf797b22cba4aba9d9b760e886178501ce4e6ef7632e43e8ab45ba78e81673</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>AKT protein</topic><topic>Antigens</topic><topic>Apoptosis</topic><topic>Biology</topic><topic>Biomarkers</topic><topic>Bladder</topic><topic>Bladder cancer</topic><topic>Breast cancer</topic><topic>Cancer</topic><topic>Carcinoma</topic><topic>Carcinoma - enzymology</topic><topic>Carcinoma - genetics</topic><topic>Carcinoma - metabolism</topic><topic>Carcinoma - pathology</topic><topic>Cell cycle</topic><topic>Cell growth</topic><topic>Cell Line, Tumor</topic><topic>Cell Movement - genetics</topic><topic>Diagnostic systems</topic><topic>Endocrinology</topic><topic>Fibroblasts</topic><topic>Focal adhesion kinase</topic><topic>Focal Adhesion Kinase 1 - genetics</topic><topic>Focal Adhesion Kinase 1 - metabolism</topic><topic>Focal Adhesion Kinase 2 - genetics</topic><topic>Focal Adhesion Kinase 2 - metabolism</topic><topic>Focal Adhesions - genetics</topic><topic>Focal Adhesions - metabolism</topic><topic>Genetic transformation</topic><topic>GRB2 Adaptor Protein - genetics</topic><topic>GRB2 Adaptor Protein - metabolism</topic><topic>Homology</topic><topic>Humans</topic><topic>Immunofluorescence</topic><topic>Insulin</topic><topic>Insulin Receptor Substrate Proteins - genetics</topic><topic>Insulin Receptor Substrate Proteins - metabolism</topic><topic>Insulin-like growth factor I</topic><topic>Insulin-Like Growth Factor I - genetics</topic><topic>Insulin-Like Growth Factor I - metabolism</topic><topic>Insulin-like growth factors</topic><topic>Invasiveness</topic><topic>Kinases</topic><topic>Localization</topic><topic>MAP kinase</topic><topic>Medical prognosis</topic><topic>Medicine</topic><topic>Mitogen-Activated Protein Kinases - genetics</topic><topic>Mitogen-Activated Protein Kinases - metabolism</topic><topic>Motility</topic><topic>Neoplasm Invasiveness</topic><topic>Nuclei</topic><topic>Pathology</topic><topic>Paxillin</topic><topic>Paxillin - genetics</topic><topic>Paxillin - metabolism</topic><topic>Phenols (Class of compounds)</topic><topic>Proline</topic><topic>Proline-rich tyrosine kinase 2</topic><topic>Prostate cancer</topic><topic>Protein-tyrosine kinase</topic><topic>Proto-Oncogene Proteins c-akt - genetics</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Receptor, IGF Type 1 - genetics</topic><topic>Receptor, IGF Type 1 - metabolism</topic><topic>Rodents</topic><topic>Signal Transduction - genetics</topic><topic>Signaling</topic><topic>Tissues</topic><topic>Transformation</topic><topic>Tumors</topic><topic>Tyrosine</topic><topic>Urinary bladder</topic><topic>Urinary Bladder Neoplasms - enzymology</topic><topic>Urinary Bladder Neoplasms - genetics</topic><topic>Urinary Bladder Neoplasms - metabolism</topic><topic>Urinary Bladder Neoplasms - pathology</topic><topic>Urology</topic><topic>Urothelial cancer</topic><topic>Urothelial carcinoma</topic><topic>Urothelium - enzymology</topic><topic>Urothelium - metabolism</topic><topic>Urothelium - pathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Genua, Marco</creatorcontrib><creatorcontrib>Xu, Shi-Qiong</creatorcontrib><creatorcontrib>Buraschi, Simone</creatorcontrib><creatorcontrib>Peiper, Stephen C</creatorcontrib><creatorcontrib>Gomella, Leonard G</creatorcontrib><creatorcontrib>Belfiore, Antonino</creatorcontrib><creatorcontrib>Iozzo, Renato V</creatorcontrib><creatorcontrib>Morrione, Andrea</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Genua, Marco</au><au>Xu, Shi-Qiong</au><au>Buraschi, Simone</au><au>Peiper, Stephen C</au><au>Gomella, Leonard G</au><au>Belfiore, Antonino</au><au>Iozzo, Renato V</au><au>Morrione, Andrea</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Proline-rich tyrosine kinase 2 (Pyk2) regulates IGF-I-induced cell motility and invasion of urothelial carcinoma cells</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-06-28</date><risdate>2012</risdate><volume>7</volume><issue>6</issue><spage>e40148</spage><pages>e40148-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The insulin-like growth factor receptor I (IGF-IR) plays an essential role in transformation by promoting cell growth and protecting cancer cells from apoptosis. We have recently demonstrated that the IGF-IR is overexpressed in invasive bladder cancer tissues and promotes motility and invasion of urothelial carcinoma cells. These effects require IGF-I-induced Akt- and MAPK-dependent activation of paxillin. The latter co-localizes with focal adhesion kinases (FAK) at dynamic focal adhesions and is critical for promoting motility of urothelial cancer cells. FAK and its homolog Proline-rich tyrosine kinase 2 (Pyk2) modulate paxillin activation; however, their role in regulating IGF-IR-dependent signaling and motility in bladder cancer has not been established. In this study we demonstrate that FAK was not required for IGF-IR-dependent signaling and motility of invasive urothelial carcinoma cells. On the contrary, Pyk2, which was strongly activated by IGF-I, was critical for IGF-IR-dependent motility and invasion and regulated IGF-I-dependent activation of the Akt and MAPK pathways. Using immunofluorescence and AQUA analysis we further discovered that Pyk2 was overexpressed in bladder cancer tissues as compared to normal tissue controls. Significantly, in urothelial carcinoma tissues there was increased Pyk2 localization in the nuclei as compared to normal tissue controls. These results provide the first evidence of a specific Pyk2 activity in regulating IGF-IR-dependent motility and invasion of bladder cancer cells suggesting that Pyk2 and the IGF-IR may play a critical role in the invasive phenotype in urothelial neoplasia. In addition, Pyk2 and the IGF-IR may serve as novel biomarkers with diagnostic and prognostic significance in bladder cancer.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22859931</pmid><doi>10.1371/journal.pone.0040148</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2012-06, Vol.7 (6), p.e40148 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1325045079 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | AKT protein Antigens Apoptosis Biology Biomarkers Bladder Bladder cancer Breast cancer Cancer Carcinoma Carcinoma - enzymology Carcinoma - genetics Carcinoma - metabolism Carcinoma - pathology Cell cycle Cell growth Cell Line, Tumor Cell Movement - genetics Diagnostic systems Endocrinology Fibroblasts Focal adhesion kinase Focal Adhesion Kinase 1 - genetics Focal Adhesion Kinase 1 - metabolism Focal Adhesion Kinase 2 - genetics Focal Adhesion Kinase 2 - metabolism Focal Adhesions - genetics Focal Adhesions - metabolism Genetic transformation GRB2 Adaptor Protein - genetics GRB2 Adaptor Protein - metabolism Homology Humans Immunofluorescence Insulin Insulin Receptor Substrate Proteins - genetics Insulin Receptor Substrate Proteins - metabolism Insulin-like growth factor I Insulin-Like Growth Factor I - genetics Insulin-Like Growth Factor I - metabolism Insulin-like growth factors Invasiveness Kinases Localization MAP kinase Medical prognosis Medicine Mitogen-Activated Protein Kinases - genetics Mitogen-Activated Protein Kinases - metabolism Motility Neoplasm Invasiveness Nuclei Pathology Paxillin Paxillin - genetics Paxillin - metabolism Phenols (Class of compounds) Proline Proline-rich tyrosine kinase 2 Prostate cancer Protein-tyrosine kinase Proto-Oncogene Proteins c-akt - genetics Proto-Oncogene Proteins c-akt - metabolism Receptor, IGF Type 1 - genetics Receptor, IGF Type 1 - metabolism Rodents Signal Transduction - genetics Signaling Tissues Transformation Tumors Tyrosine Urinary bladder Urinary Bladder Neoplasms - enzymology Urinary Bladder Neoplasms - genetics Urinary Bladder Neoplasms - metabolism Urinary Bladder Neoplasms - pathology Urology Urothelial cancer Urothelial carcinoma Urothelium - enzymology Urothelium - metabolism Urothelium - pathology |
| title | Proline-rich tyrosine kinase 2 (Pyk2) regulates IGF-I-induced cell motility and invasion of urothelial carcinoma cells |
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